Millions of Americans develop chest pain suggestive of coronary heart disease each year and often require non-invasive diagnostic testing. However, currently available tests are imprecise, robust evidence regarding optimal test choice is limited, and testing costs are rising disproportionately. Further, the role of new technology such as coronary computed tomographic angiography (CTA) is uncertain. In response, the PROspective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) Trial will test the hypothesis that an initial 'anatomic' testing strategy (using CTA) is clinically superior to usual care or an initial 'functional' stress testing strategy (using physician-selected stress imaging (echocardiography or nuclear) or exercise electrocardiography)) in low-intermediate coronary artery risk patients with chest pain, and will reduce the composite primary endpoint of death, myocardial infarction, major peri-procedural complications and hospitalization for unstable angina. This 150 site pragmatic trial will randomize 10,000 symptomatic patients with clinically determined, low-intermediate risk for CAD over 24 months. All subsequent diagnostic and therapeutic management will be based on the latest clinical practice guideline recommendations and will be at the discretion of the treating care team. Patients will be followed for up to 48 months (median 2.5 years). The trial design is carefully constructed to ensure the broadest possible applicability of results by incorporating the full spectrum of practice settings, caregiver specialties, and types of tests which are immediately relevant to the clinical decisions needed to care for the vast majority of chest pain patients nationwide. Projecting a 9% event rate in the functional testing or usual care arm, enrollment of 5,000 patients in each testing arm will provide 90% power for detecting a 20% relative reduction in the composite primary endpoint. Secondary endpoints include components of the primary endpoint as well as 1) medical costs, resource utilization, cost effectiveness; 2) health related quality of life. This proposal includes the lead Clinical Coordinating Center (CCC; Pamela S Douglas, PI), a Statistical and Data Coordinating Center (SDCC; Kerry L Lee, PI), an Economics and Quality of Life (EQOL; Daniel B Mark, PI), and a Diagnostic Test Core (Dx Core; Udo Hoffmann, PI). This experienced multi-speciality team will deliver the integrated services vital to PROMISE trial, including faculty and operational leadership, imaging and testing expertise, site management, patient follow up, statistical analysis and data management. Although costs of care are extremely important, only demonstration of clinical superiority in real-world settings will change practice or justify use and reimbursement of a new technology such as CTA. PROMISE, as the first large randomized comparison of two diagnostic testing strategies for patients with suspected CAD, will provide the critical evidence regarding clinical outcomes and costs of alternative approaches necessary to shape clinical practice recommendations and health care policy in patients with chest pain for years to come.